CAR T cells vs bispecific antibody as third- or later-line large B-cell lymphoma therapy: a meta-analysis.

This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third or subsequent lines in R/R DLBCL. Random-effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% confidence interval [CI], 0.29-0.43), compared with 0.51 (95% CI, 0.46-0.56) for CAR T-cell therapy (P < .01). This superiority persisted when comparing the CAR T-cell-naive patients within the bispecific antibody group, with a CR rate of 0.37 (95% CI, 0.32-0.43). Multivariable meta-regression also revealed better efficacy of CAR T cells with adjustment for the proportion of double-hit lymphoma. The pooled 1-year progression-free survival rate mirrored these findings (0.32 [95% CI, 0.26-0.38] vs 0.44 [95% CI, 0.41-0.48]; P < .01). For adverse events of grade ≥3, the bispecific antibody had incidences of 0.02 (95% CI, 0.01-0.04) for cytokine release syndrome, 0.01 (95% CI, 0.00-0.01) for neurotoxicity, and 0.10 (95% CI, 0.03-0.16) for infections. The CAR T cell had rates of 0.08 (95% CI, 0.03-0.12), 0.11 (95% CI, 0.06-0.17), and 0.17 (95% CI, 0.11-0.22), respectively, with significant differences observed in the first 2 categories. In summary, CAR T-cell therapy outperformed bispecific antibody in achieving higher CR rates, although with an increase in severe adverse events.

Kim J ，Cho J ，Lee MH ，Yoon SE ，Kim WS ，Kim SJ ... -  《-》

CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.

CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia. In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity. Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata. Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia. Children's Hospital of Philadelphia Frontier Program.

Leahy AB ，Newman H ，Li Y ，Liu H ，Myers R ，DiNofia A ，Dolan JG ，Callahan C ，Baniewicz D ，Devine K ，Wray L ，Aplenc R ，June CH ，Grupp SA ，Rheingold SR ，Maude SL ... -  《-》

Safety and activity of CTX130, a CD70-targeted allogeneic CRISPR-Cas9-engineered CAR T-cell therapy, in patients with relapsed or refractory T-cell malignancies (COBALT-LYM): a single-arm, open-label, phase 1, dose-escalation study.

Effective treatment options are scarce for relapsed or refractory T-cell lymphoma. This study assesses the safety and activity of CTX130 (volamcabtagene durzigedleucel), a CD70-directed, allogeneic chimeric antigen receptor (CAR) immunotherapy manufactured from healthy donor T cells, in patients with relapsed or refractory T-cell lymphoma. This single-arm, open-label, phase 1 study was done at ten medical centres across the USA, Australia, and Canada in patients (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma, who had received at least one or at least two previous systemic therapy lines, respectively, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients underwent lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 × 107 CAR+ T cells (dose level 1) to 9 × 108 CAR+ T cells (dose level 4). The primary endpoint was the incidence of adverse events, defined as dose-limiting toxicities occurring within 28 days post-infusion. Secondary endpoints included objective response rate. Safety and activity analyses were performed on data from all patients who received CTX130. The trial is registered with ClinicalTrials.gov (NCT04502446) and EudraCT (2019-004526-25) and is closed to enrolment. Between Aug 28, 2020, and May 30, 2023, 41 patients were enrolled and 39 (95%) received CTX130. The median patient follow-up was 7·4 months (IQR 3·1-12·2). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. The median number of previous lines of anticancer therapy was 2·5 (IQR 1·3-4·0) for patients with peripheral T-cell lymphoma and 5·0 (IQR 5·0-7·0) for patients with cutaneous T-cell lymphoma. Cytokine release syndrome was the most common adverse event, occurring in 26 (67%) of 39 patients (23 were grade 1-2, two were grade 3, and one was a grade 4 dose-limiting toxicity at dose level 4). Grade 1-2 neurotoxic events were observed in four (10%) of 39 patients. The most common grade 3-4 adverse events were neutropenia (14 [36%]), anaemia (11 [28%]), and thrombocytopenia (six [15%]). Serious adverse events occurred in 25 (64%) patients, with CTX130-related serious adverse events in 14 (36%) patients, the most common related serious adverse event being cytokine release syndrome in 11 (28%) patients. 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. 18 of 39 patients (46·2% [95% CI 30·1-62·8) had an objective response. Of those treated at dose level 3 and higher, 16 of 31 patients (51·6% [33·1-69·8]) had objective responses, including six (19·4% [7·5-37·5]) with complete response and ten (32·3% [16·7-51·4]) with a partial response. In patients with heavily pretreated T-cell lymphoma, CTX130 showed manageable safety and a promising objective response rate. This study shows that allogeneic, readily available CAR T cells can be safely given to patients with relapsed or refractory T-cell lymphoma. A next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development. CRISPR Therapeutics.

Iyer SP ，Sica RA ，Ho PJ ，Prica A ，Zain J ，Foss FM ，Hu B ，Beitinjaneh A ，Weng WK ，Kim YH ，Khodadoust MS ，Huen AO ，Williams LM ，Ma A ，Huang E ，Ganpule A ，Nagar SD ，Sripakdeevong P ，Cullingford EL ，Karnik S ，Dequeant ML ，Patel JN ，He XS ，Li Z ，He QA ，Mendonez JH ，Keegan A ，Horwitz SM ... -  《-》

Anti-CD19 CAR-T Cell Therapy in Elderly Patients: Multicentric Real-World Experience from GETH-TC/GELTAMO.

Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies.

Bailén R ，Iacoboni G ，Delgado J ，López-Corral L ，Hernani-Morales R ，Ortiz-Maldonado V ，Guerreiro M ，Caballero AC ，Guerra-Domínguez ML ，Sánchez-Pina JM ，Peña M ，Torrent A ，Pérez-Martínez A ，Bastos-Oreiro M ，Reguera-Ortega JL ，Martín A ，Hernandez-Boluda JC ，Martínez-Cibrián N ，Sanz J ，Briones J ，Henriquez HL ，Calbacho M ，Mussetti A ，Sancho JM ，Barba P ，Kwon M ，GETH-TC (Spanish Group of Stem Cell Transplantation and Cell Therapy) and GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation) ... -  《-》

In vitro functional validation of anti-CD19 chimeric antigen receptor T cells expressing lysine-specific demethylase 1 short hairpin RNA for the treatment of diffuse large B cell lymphoma.

Chimeric antigen receptor T (CAR-T) cell therapy is more effective in relapsed or refractory diffuse large B cell lymphoma (DLBCL) than other therapies, but a high proportion of patients relapse after CAR-T cell therapy owing to antigen escape, limited persistence of CAR-T cells, and immunosuppression in the tumor microenvironment. CAR-T cell exhaustion is a major cause of relapse. Epigenetic modifications can regulate T cell activation, maturation and depletion; they can be applied to reduce T cell depletion, improve infiltration, and promote memory phenotype formation to reduce relapse after CAR-T cell therapy. We propose to develop and validate in vitro the function of novel CAR-T cells for the treatment of DLBCL, which simultaneously express an anti-CD19 CAR with lysine-specific demethylase 1 (LSD1) short hairpin (sh)RNA to prevent depletion and prolong the survival of CAR-T cells. We designed an shRNA sequence targeting LSD1 mRNA, and created a vector with the following elements: the U6 promoter driving expression of the LSD1 shRNA sequence, the EF1a promoter driving a second-generation anti-CD19 CAR sequence encoding an anti-CD19 single-chain variable fragment (FMC63), the CD8 hinge and transmembrane structural domains, the CD28 co-stimulatory structural domain, and the CD3ζ-activating structural domain. The MFG-LSD1 shRNA anti-CD19 CAR plasmid was first constructed, then packaged in retroviral vectors and transduced into human primary peripheral blood mononuclear cell-derived T cells to generate the corresponding CAR-T cells. We examined by flow cytometry the efficiency of two CAR-T cells in killing U-2932 cells (a human DLBCL line) upon co-culture with RNAU6 anti-CD19 CAR-T cells or LSD1 shRNA anti-CD19 CAR-T cells. We analyzed Ki-67 staining of the CAR-T cells by flow cytometry on days 0, 5, and 10, and counted the cells to assess expansion. We also used flow cytometry to detect the central memory T cell (TCM) proportion. We detected the expression of the CAR in the CAR-T cells by flow cytometry, and observed transduction rates of 31.5% for RNAU6 anti-CD19 CAR-T cells and 60.7% for LSD1 shRNA anti-CD19 CAR-T cells. The killing efficiency of LSD1 shRNA anti-CD19 CAR-T cells was significantly higher than that of RNAU6 anti-CD19 CAR-T cells at the low effector target ratio. We further found that LSD1 shRNA anti-CD19 CAR-T cells secreted more IFN-γ and granzyme B than RNAU6 anti-CD19 CAR-T cells. CAR-T cells proliferated after U-2932 cell stimulation and were able to sustain proliferation. After stimulation via U-2932 cell co-culture, both RNAU6 anti-CD19 CAR-T and LSD1 shRNA anti-CD19 CAR-T populations had increased proportions of cells with the TCM phenotype, with a higher percentage among LSD1 shRNA anti-CD19 CAR-T cells. We developed a novel, feasible CD19-LSD1 shRNA CAR-T cell strategy for the treatment of DLBCL. Our in vitro assay results showed that LSD1 shRNA anti-CD19 CAR-T cells more effectively killed target cells than RNAU6 anti-CD19 CAR-T cells, and developed a higher proportion of TCM phenotype cells. LSD1 shRNA anti-CD19 CAR-T cells may represent a potential treatment for DLBCL.

Guo Z ，He M ，Liu N ，Yang Y ，Sun R ，Wang J ，Wang Q ... -  《Frontiers in Immunology》